KR20120098489A - Composition comprising the pyrezole derivatives for prevention and treatment of cardiovascular diseases - Google Patents

Abstract

PURPOSE: A composition containing pyrazole derivative compounds and pharmaceutically acceptable salt thereof is provided to effectively suppress reactive oxygen regeneration and to prevent or treat cardiovascular disease without side effects. CONSTITUTION: A composition for preventing or treating cardiovascular diseases contains a compound of chemical formula 1. A composition for preventing or treating cardiovascular diseases contains pharmaceutically acceptable salt of the compound. A pharmaceutical composition for preventing or treating cardiovascular diseases contains a compound of chemical formula I or pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating cardiovascular diseases contains a compound of chemical formula A or pharmaceutically acceptable salt thereof. The pharmaceutical composition is manufactured in the form of powder, granules, tablets, capsuels, suspensions, emulsions, oral formulation of syrups or aerosol, external use formulation, supporsitory, or sterilization injection solution.

Description

Composition comprising the pyrezole derivatives for prevention and treatment of cardiovascular diseases}

The present invention relates to a composition for preventing and treating cardiovascular diseases comprising a pyrazole derivative.

Atherosclerosis, especially atherosclerosis, means that fatty substances (plaque) containing cholesterol, phospholipids, and calcium accumulate in the vascular lining, causing the arteries to harden, lose elasticity and become narrower, impeding blood supply or increasing pressure, resulting in arterial rupture and detachment. It tells you what happens. In particular, atherosclerosis causes narrowing of the arteries (narrowing of blood vessels), resulting in a decrease in blood supply and a lack of nutrients and oxygen, which is a major cause of cardiovascular disease (Libby P, et al., Circulation, 86 (6), 47-52, 1992; Lundgren CH, et al., Circulation, 90 (4), 1927-1934, 1994; Harker, et al., Ann.NY Acad. Sci., 275, 321-329 , 1976). The cardiovascular disease is a disease including cardiovascular diseases such as atherosclerosis, heart failure, hypertensive heart disease, arrhythmia, congenital heart disease, myocardial infarction and angina, and stroke and peripheral vascular disease. Ischemic cardiovascular disease.

At present, the treatment of cardiovascular diseases caused by atherosclerosis can be divided into treatment for angiogenesis and prevention of vascular narrowing and prevention for restenosis through inhibition of proliferation of vascular smooth muscle cells.

Percutaneous coronary angioplasty is a method of dilatating a narrowed coronary artery without surgery. The surgical methods include percutaneous coronary balloon dilatation and percutaneous coronary stent insertion. Percutaneous coronary balloon dilatation inserts a guided catheter through the artery of the thigh or arm and places it at the inlet of the coronary artery with a lesion through the aorta. It is a method of improving the blood flow of the coronary arteries by expanding the balloon and expanding the narrowed coronary arteries by squeezing plaque or the like after placing the constriction. In addition, the stent implantation is to place a wire mesh coated balloon in the stenosis, and then expand the balloon to apply a wire mesh to the inner wall of the coronary artery.The stent has a lower incidence of restenosis than when only balloon dilatation is performed. It is used for the treatment of complications that occur when the balloon is inflated because it has the property of supporting the inner wall. The interventional procedure using coronary angioplasty is simpler than the surgical method, reduces the risk of general anesthesia, and has a high success rate.

However, in 10-80% of patients treated with coronary angioplasty, vascular endothelial damage, vascular thrombosis, vascular smooth muscle and fibroblast migration and monocyte and lymphocyte infiltration, new heart Restenosis occurs through formation of neointima, accumulation of extracellular matrix (reendothelialization), and apoptosis. Restenosis is most likely to include diabetes, old age, recently started angina or unstable angina (Leimgruber PP et al., Circulation, vol. 73, 710, 1986).

New Percutaneous Transluminal Coronary Angioplasty (ATC), including atherostomy, laser angioplasty, rotablator, cutting balloon angioplast and radiation to prevent coronary restenosis Equipment has been introduced, and molecular biological therapies such as antiplatelet agents, antithrombotic agents, vasodilators, cell proliferation inhibitors, lipid metabolism enhancers and antioxidants have been developed and attempted. Among these, systemic drug therapy such as oral administration and intravenous administration has been reported to be the most easily applicable treatment, or to prevent restenosis in animal experiments. The side effects of the drug did not prevent restenosis in most clinical trials. Theoretically, restenosis occurs only in the coronary arteries of the localized site where PTCA has been applied, so local drug therapies can be used to prevent high restenosis and to provide site-specific high doses rather than systemic drug therapy. therapy is more useful. Recently, in order to directly administer the drug to the PTCA site, a double-balloon catheter, a dispatch or a microporous balloon has been developed and used in clinical practice. Attempts have been made to treat slow release microspheres or stents with drugs.

Recently, studies have reported that reactive oxygen species (ROS) induced by oxidative stress have been linked to cardiovascular disease. The stable oxygen (triplet oxygen) is a reactive reactive oxygen such as superoxide radicals, hydroxy radicals, hydrogen peroxide due to enzymatic system, reduction metabolism, chemicals, pollutants, environmental and biochemical factors such as photochemical reactions Oxygen species (ROS) are known to oxidize various cell components, such as lipids, proteins, nucleic acids, and DNA, causing inflammation or damaging many organs (Beckman, JS et al., Proc. Natl. Acad. Sci. USA, 87, pp 1620-1624, 1990: Sagar, S. et al., Mol. Cell Biochem., 111, pp 103-108, 1992: Ames, BN et al., Proc. Natl. Acad. USA, 90, pp7915 -7922, 1993). For example, superoxide anion (O2), hydrogen peroxide (H2O2), hydroxyl radical (OH), singlet oxygen (1O2), alkoxyl produced by lipid peroxidation Alkoxyl radicals (RO?), Peroxyl radicals (ROO?) And nitrogen peroxide ions (ONOO-). The action of these free radicals affects the action of antioxidant enzymes such as superoxide dismutase (SOD), catalase, and peroxidase, and the antioxidants such as vitamins C, E, and glutathione. However, when this biodefense occurs abnormally or when exposed to excessive free radicals, the balance is broken and the free radicals irreversibly destroy substrates, proteins and DNA, resulting in various diseases. In particular, it has been reported to be an important cause of cardiovascular disease, such as multiple atherosclerosis (Griffiths and Lunec, FEBS Lett., 388, pp161-164, 1996: Squadrito, GL et al., Free Radic. Biol. Med., 25, pp392-403, 1998: Choi, JS et al., Phytochem.Res., 16, pp232-235, 2002: Beckman, JS et al., Proc. Natl. Acad. Sci USA, 87, pp 1620-1624, 1990).

Accordingly, the present inventors have tried to find a substance useful for the prevention and treatment of cardiovascular disease, and as a result, the pyrazole derivatives of the present invention found that not only inhibits the proliferation and migration of smooth muscle cells, but also has an excellent activity of inhibiting the production of free radicals. The present invention has been completed by confirming that it can be used for the prevention or treatment of diseases.

It is an object of the present invention to provide a composition for preventing and treating cardiovascular diseases comprising a pyrazole derivative.

Another object of the present invention is to provide a method for removing vascular narrowing by administering the composition to a subject.

Another object of the present invention is to provide a drug delivery device for topical administration of the composition.

The present invention provides a pharmaceutical composition for preventing or treating cardiovascular disease, comprising a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where

X is -CH- or nitrogen;

R ₁ is a hydrogen atom or isopropyloxycarbonyloxymethyl;

R ₂ is a hydrogen atom, straight or branched chain alkyl of C 1 to C 4, substituted or unsubstituted benzyl;

R ₃ is phenyl, nitrophenyl, substituted or unsubstituted phenylethenyl or substituted or unsubstituted diphenylethenyl;

Wherein if R ₁ and R ₂ are hydrogen atoms, R ₃ is phenyl, nitrophenyl or substituted or unsubstituted diphenylethenyl,

The substituent is nitro, hydroxy or methoxy.

In the compound represented by Formula 1, preferably, when X is -CH- and R ₁ and R ₂ are hydrogen atoms, R ₃ is substituted or unsubstituted diphenylethenyl or X is nitrogen atom and R is _{When 1} and R ₂ is a hydrogen atom, R ₃ may be substituted or nitrophenyl or unsubstituted diphenylethenyl, and the salt of the compound represented by Formula 1 is that when R ₁ and R ₂ are hydrogen atoms, R ₃ may be phenyl, nitrophenyl or substituted or unsubstituted diphenylethenyl.

The compound represented by Formula 1 may be a compound selected from the compounds listed below:

1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol (211);

1- (pyridin-2-yl) -3-phenyl-4-benzyl- 1H -pyrazol-5-ol 212;

1- (pyridin-2-yl) -3-phenyl-4- (4-nitrobenzyl) 1H -pyrazol-5-ol (225);

Hydrochloride 278 of 1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol;

1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -5 (isopropyloxycarbonyloxymethyloxy) pyrazole 306;

Hydrochloride 308 of 1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E -ethenyl] -4-benzyl- 1H -pyrazole-5-ol;

1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E-ethenyl] -4-benzyl-5-hydroxypyrazole 274;

3- (4-nitrophenyl) -3- [2- (pyrimidin-2-yl) hydrazono] propionic acid ethyl ester;

1- (pyrimidin-2-yl) -3- (4-nitrophenyl) -5-1H -pyrazole-5-ol (105);

1- (pyridin-2-yl) -3- (1,2-diphenyl-butenyl -E-) - 1H - pyrazol-5-ol (263);

Hydrochloride 305 of 1- (pyridin-2-yl) -3-phenyl- 1H -pyrazole-5-ol;

3- (4-methoxy-phenylamino) - 1H - pyrazol-5-ol (15) or

4-hexylidene-1-phenyl-3- (pyridin-2-yl) - 1H - pyrazol-5-ol (213).

On the other hand, the compound represented by the formula (1) or pharmaceutically acceptable salt thereof is a step of dropping the compound represented by the formula (2) and the compound represented by the formula (3) dropwise to a polar organic solvent; And

It may be prepared by a manufacturing method comprising the step of heating the polar organic solvent containing the compound represented by Formula 2 and Formula 3.

[Formula 2]

(3)

[Formula 1]

In this formula,

X is -CH- or nitrogen;

R _h is a C1-C4 straight or branched alkyl group;

R ₁ is a hydrogen atom or isopropyloxycarbonyloxymethyl;

R ₂ is a hydrogen atom, straight or branched chain alkyl of C 1 to C 4, substituted or unsubstituted benzyl;

R ₃ is phenyl, nitrophenyl, substituted or unsubstituted phenylethenyl or substituted or unsubstituted diphenylethenyl;

Wherein if R ₁ and R ₂ are hydrogen atoms, R ₃ is phenyl, nitrophenyl or substituted or unsubstituted diphenylethenyl,

The substituent is nitro, hydroxy or methoxy.

In the preparation of Chemical Formula 1, a-substituted β-keto ester which is a compound represented by Chemical Formula 2 used as a starting material may be commercially available. Or J. Org. Chem., Vol. 43, No. 10, 1978, 2087-2088. Specifically, the product of the reaction of a commercially available acyl chloride derivative with Meldrum's acid may be prepared in an organic solvent such as methanol or ethanol. Heat reflux can produce the β-keto ester. a-substituted β-keto esters are described in J. Chem. Soc., Perkin Trans. It can be prepared according to the method described in 1, 1986, 1139-1143, specifically, it can be easily prepared by the reaction of β-keto ester and alkyl halide in the presence of potassium carbonate or cesium carbonate.

The compound represented by Chemical Formula 3 as a reactant may be commercially available, and about 1 to 3 molar equivalents of the compound represented by Chemical Formula 3 may be used with respect to 1 molar equivalent of the compound represented by Chemical Formula 2 as a starting material. Preferably about 1 to 1.3 molar equivalents may be used.

The polar organic solvent may be C1-C4 alcohol or acetic acid or a mixture thereof, such as methanol, ethanol, n-propanol, i-isopropanol, n-butanol, t-butanol, and preferably ethanol or acetic acid.

A salt of the compound represented by Chemical Formula 1 may be prepared by reacting the compound represented by Chemical Formula 1 with an acidic substance. The acidic substance is not particularly limited as long as it is a substance capable of reacting with the compound represented by Chemical Formula 1 to form a salt. For example, the acidic substance may be inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, Organic acids such as manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, methane Sulfonic acids made of sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like, and the like, and hydrochloric acid is preferable.

The compound represented by Formula 2 and the compound represented by Formula 3 may be added dropwise to the polar organic solvent at -4 ℃ to 10 ℃.

The organic solvent including the compound represented by Formula 2 and the compound represented by Formula 3 may be heated at a temperature capable of refluxing the solvent, and preferably, heated at about 100 to about 130 ° C.

The organic solvent including the compound represented by Formula 2 and the compound represented by Formula 3 may be heated for about 10 minutes to 72 hours.

The compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 may be reacted under an organic solvent to prepare a compound represented by Chemical Formula 4 below.

[Formula 4]

Where

R ₂ is a hydrogen atom, straight or branched chain alkyl of C 1 to C 4, substituted or unsubstituted benzyl;

R ₃ is phenyl, nitrophenyl, substituted or unsubstituted phenylethenyl or substituted or unsubstituted diphenylethenyl;

Wherein the substituent is nitro, hydroxy or methoxy and if R ₂ is a hydrogen atom then R ₃ is Phenyl, nitrophenyl or substituted or unsubstituted diphenylethenyl.

The compound represented by Chemical Formula 4 is reacted with a halide compound such as isopropyloxycarbonyloxymethyl iodide, isopropyloxycarbonyloxymethyl chloride or isopropyloxycarbonyloxymethyl bromide in the presence of a base to In the compound to be represented, a compound represented by Formula 1 having an isopropyloxycarbononyloxymethyloxy group bonded to a carbon position of pyrazole 5 may be prepared.

In the reaction of the compound represented by Formula 4 with the halide compound, the base is a metal salt of carbonate such as 4-dimethylaminopyridine (DMAP), pyridine, triethylamine, imidazole, potassium carbonate, sodium carbonate, calcium carbonate Or mixtures thereof. The base may be used in an amount of about 2 to about 3 molar equivalents based on 1 molar equivalent of the compound represented by Formula 2.

In the reaction of the compound represented by Formula 4 with the halide compound, the reaction solvent may be a mixture of water and an organic solvent, preferably water and methylene chloride, ethyl ether, ethyl acetate, tetrahydrofuran (THF) and DMF (N, N'-Dimethylformamide may be a mixture of at least one organic solvent selected from, and more preferably, may be a mixture of water and methylene chloride.

The reaction of the compound represented by Formula 4 with the halide compound may be performed under a phase transfer catalyst. In such a case, the amine group at the 2-position of the pyrazole group can suppress the generation of alkylated impurities, thereby obtaining a compound represented by Chemical Formula 1 with higher purity.

In the reaction of the compound represented by Formula 4 with the halide compound, the reaction temperature is preferably about 0 to about 40 ℃, more preferably 15 to 30 ℃, the reaction time is preferably about 10 to 12 hours, Depending on the reaction rate, the reaction temperature can be further increased and the reaction time can be further increased.

The present invention provides a pharmaceutical composition for preventing or treating cardiovascular disease, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

(I)

In this formula,

X is -CH- or nitrogen;

R _a is a hydrogen atom, an acetyl group, a tri (C 1 -C 4) alkylsilaneyl group, a diphenylboranyl group or a (t-butoxy) carbonyl group;

R _b , R _c or R _d are each a hydrogen atom, a halogen atom (F, Cl, Br, I) halo (C 1 -C 3) alkyl group, (C 2 -C 6) alkoxy group, benzo [d] [1,3] diox Seam group, a substituted or unsubstituted biphenyl group, or a substituted or unsubstituted (C6-C10) aryl group, wherein the substituent is a halogen atom, a (C1-C4) alkyl amine group, a halo (C1-C3) alkyl group, (C1- C6) Alkoxy, phenoxy, benzyloxy, formyl or phenyl substituted with halogen atoms, but R _b , R _c and R _d are not all hydrogen atoms.

The compound represented by Formula I may be a compound selected from the compounds listed below:

1- (pyridin-2-yl) -3- (3- (trifluoromethyl) phenyl) -1H-pyrazol-5-ol,

1- (pyridin-2-yl) -3- (4- (trifluoromethyl) phenyl) -1H-pyrazol-5-ol,

3- (3-nitrophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

1- (pyridin-2-yl) -3- (3,4,5-trimethoxyphenyl) -1H-pyrazol-5-ol,

3- (2-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (2-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (2-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (3-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (4-iodophenyl) -1- (pyrimidin-2-yl) -1H-pyrazole-5-ol,

2- (3- (4-iodophenyl) -5- (triisopropylsilyloxy) -1H-pyrazol-1-yl) pyridine,

3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

t-butyl 3- (2-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (3-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (4-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (4-iodophenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl carbonate,

3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl acetate,

3- (biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

t-butyl 3- (4- (naphthalene) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (3 '-(dimethylamino) biphenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

3- (2- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (3'-phenylbiphenyl-2-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (4 '-(benzyloxy) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (4'-bromobiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

t-butyl 3- (3'-formylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (2'-phenoxybiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

3- (3- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (3'-phenylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

t-butyl 3- (3- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (3 '-(dimethylamino) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

t-butyl 3- (4'-methoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

3- (4 '-(benzyloxy) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (4'-bromobiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (3'-formylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

t-butyl 3- (2'-phenoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate,

3- (biphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

3- (3'-phenylbiphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate,

2- (3- (4'-bromobiphenyl-4-yl) -5- (triisopropylsilyloxy) -1H-pyrazol-1-yl) pyridine,

2- (3- (biphenyl-4-yl) -5- (diphenylboryloxy) -1H-pyrazol-1-yl) pyridine,

3- (biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3 '-(dimethylamino) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (2- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3'-phenylbiphenyl-2-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4 '-(benzyloxy) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4'-bromobiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3'-formylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (2'-phenoxybiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3'-phenylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3 '-(dimethylamino) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4'-methoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4 '-(benzyloxy) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4'-bromobiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3'-formylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (2'-phenoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (biphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol,

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol,

3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3-phenyl-4-propyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol,

4-benzyl-3-phenyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol.

Meanwhile, the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof may be prepared by the following method.

Specifically, the compound represented by the following formula (I-1) or a pharmaceutically acceptable salt thereof corresponding to the formula (I) is a compound of formula (I-1) by heating the compound of formula (II) and formula (III) in a polar organic solvent It can be prepared by the method for preparing.

≪ RTI ID = 0.0 &

[Formula III]

(I-1)

Wherein X is -CH- or nitrogen;

R is a (C1-C4) alkyl group;

R _b , R _c or R _d are each a hydrogen atom, a halogen atom, a halo (C 1 -C 3) alkyl group or a (C 2 -C 6) alkoxy group, but R _b , R _c and R _d are not all hydrogen atoms.

In the preparation method of Chemical Formula I-1, β-keto ester which is a compound of Formula II used as a starting material may be commercially available. Or J. Org. Chem., Vol. 43, No. 10, 1978, 2087-2088. Specifically, the product produced by reacting a commercially available acyl chloride derivative with Meldrum's acid may be heated to reflux in a methanol or ethanol solvent. It can manufacture.

In the preparation method of Chemical Formula I-1, a compound of Chemical Formula III, which is a reactant, may be commercially available, and its amount may be used in an amount of about 1 to 3 molar equivalents relative to the molar equivalent of Compound II of the starting material. 1 to 1.3 molar equivalents are preferred.

In the method for preparing the compound of Formula I-1, the polar organic solvent is preferably selected from among C1-C4 alcohols such as methanol, ethanol, n-propanol, i-isopropanol, n-butanol, t-butanol, acetic acid and mixtures thereof. Do. More preferred is ethanol or acetic acid.

In the method for preparing the compound of Formula I-1, the heating is preferably a temperature at which the solvent can be refluxed, for example, it is preferably carried out at about 100 to about 130 ℃.

In the method for preparing the compound of Formula I-1, the reaction time is preferably performed for 2 to 72 hours.

Compound represented by the compound of formula (I-2) or a pharmaceutically acceptable salt thereof corresponding to the formula (I) is acetyl chloride, tris (C1-C4) alkylsilyl chloride or di It may be prepared by a method of preparing a compound of formula (I-2) by reacting with one selected from -t-butyldicarbonate (BOC ₂ O).

(I-1)

[Formula I-2]

Wherein X is -CH- or nitrogen;

R _a is an acetyl group, a tri (C1-C4) alkylsilyl group, or a (t-butoxy) carbonyl group;

R _b , R _c or R _d are each a hydrogen atom, a halogen atom, a halo (C 1 -C 3) alkyl group or a (C 2 -C 6) alkoxy group, but R _b , R _c and R _d are not all hydrogen atoms.

In the method for preparing a compound of Chemical Formula I-2, the amount of reactant acetyl chloride, tris (C1-C4) alkylsilyl chloride or di-t-butyldicarbonate (BOC ₂ O) may be used as a starting material of Chemical Formula I-1. It is preferable to use 1.2 to 5 equivalents relative to the equivalent of the compound.

In the method for preparing the compound of Formula I-2, the base is preferably selected from 4-dimethylaminopyridine (DMAP), pyridine, triethylamine and imidazole, and 4-dimethylaminopyridine is more preferred as a catalyst. The base is preferably used in an amount of 2 to 3 equivalents, and in the case of a catalyst for use of the compound of the starting material I-1, it is preferable to use about 0.01 to 0.5 molar equivalents relative to molar equivalents, and more than 0.05 molar equivalents. desirable.

In the method for preparing the compound of Formula (I-2), the reaction solvent may be an organic solvent such as methylene chloride, ethyl ether, ethyl acetate, THF (tetrahydrofuran), DMF (N, N'-Dimethylformamide) and the like, for example, methylene Chloride is more preferred.

In the method for preparing the compound of Formula I-2, the reaction temperature is preferably about 0 to about 40 ℃, more preferably 15 to 30 ℃, the reaction time is preferably about 10 to 12 hours, depending on the reaction rate It can raise the temperature further and increase the reaction time.

In addition, the compound represented by the compound of formula (I-3) or a pharmaceutically acceptable salt thereof corresponding to the formula (I) by reacting a compound of formula (I-2) with a compound of formula (IV) in the presence of a palladium metal catalyst and a base It may be prepared by a method of preparing a compound of Formula I-3.

[Formula I-2]

In formula (I-2), X is -CH- or nitrogen;

R _a is hydrogen, an acetyl group, a tri (C1-C4) alkylsilaneyl group, a (t-butoxy) carbonyl group;

R _b , R _c or R _d are each a hydrogen atom or a halogen atom, but R _b , R _c and R _d are not all hydrogen atoms,

(IV)

In the above formula (IV)

R _e , R _f or R _g are each a hydrogen atom or a halogen atom, a (C1-C4) alkyl amine group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy, phenoxy group, benzyloxy, formyl group, a phenyl group Or a phenyl group substituted with a halogen atom, R _e and R _f or R _f and R _g are —OCH ₂ O— or —CH═CH—CH═CH—, but R _e , R _f and R _g are not all hydrogen atoms; ,

[Formula I-3]

In formula (I-3), X is -CH- or nitrogen;

R _a is hydrogen, an acetyl group, a tri (C 1 -C 4) alkylsilaneyl group, a diphenylboranyl group or a (t-butoxy) carbonyl group;

R _e , R _f or R _g are each a hydrogen atom, a halogen atom, a (C1-C4) alkyl amine group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy, phenoxy group, benzyloxy, formyl group, or a phenyl group Or a phenyl group substituted with a halogen atom, R _e , and R _f or R _f and R _g are -OCH ₂ O- or -CH = CH-CH = CH-, but R _e , R _f and R _g are all hydrogen atoms; no.

In the method for preparing the compound of Formula I-3, the compound of Formula IV, which is a reactant, may be purchased and used commercially. The use equivalent of the compound of formula IV as a reactant is preferably about 1 to 5 equivalents, more preferably 2 to 3 equivalents, relative to the compound equivalent of formula I-2.

In the method for preparing the compound of Formula (I-3), the palladium metal catalyst is PdCl ₂ (dppf) and dppf (1,1'-Bis (diphenylphosphino) ferrocene) or as a possible Pd catalyst Pd (PPh ₃ ) ₄ , Pd (OAc _{) 2, Pd (dba) CHCl} 3, such as the one available, PdCl ₂ (dppf), and dppf (1,1'-Bis (diphenylphosphino) is more preferably a ferrocene). Herein, the amount of the palladium metal catalyst used is preferably 0.01 to 0.5 equivalents, and more preferably 0.03 to 0.1 equivalents, based on the equivalent use of the compound of formula (I-2). In addition, PdCl ₂ (dppf) and dppf (1,1'-Bis (diphenylphosphino) ferrocene) is preferably used in comparison to 2: 1 equivalent.

In the method for preparing the compound of Formula I-3, the base is It is preferably selected from K ₃ PO ₄ , K ₂ CO ₃ , Ba (OH) ₂ , Cs ₂ CO ₃ , and the amount of base used is relative to the molar equivalent of the compound of Formula I-2. 1 to 3 molar equivalents are preferred.

In the method for preparing the compound of Formula I-3, the reaction temperature is preferably 90 to 110 ℃, the reaction solvent is preferably selected from 1,4-dioxane, THF, DMF, Toluene.

In addition, the compound represented by the compound of formula (I-4) or a pharmaceutically acceptable salt thereof corresponding to formula (I) is prepared by converting the compound of formula (I-3) to the compound of formula (I-4) in the presence of an organic acid Can be.

[Formula I-3]

[Formula I-4]

Wherein X is -CH- or nitrogen;

R _a is an acetyl group, a tri (C1-C4) alkylsilaneyl group or a (t-butoxy) carbonyl group;

R _e , R _f or R _g are each a hydrogen atom, a halogen atom, a (C1-C4) alkyl amine group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy, phenoxy group, benzyloxy, formyl group, or a phenyl group Or a phenyl group substituted with a halogen atom, or R _e and R _f or R _f and R _g are —OCH ₂ O— or —CH═CH—CH═CH—, or R _e , R _f and R _g Are not all hydrogen atoms.

In the method for preparing the compound of formula (I-4), the organic acid is preferably selected from trifluoroacetic acid, trichloroacetic acid, HF and HCl, more preferably trifluoroacetic acid. The amount of the organic acid used is preferably about 2 to 10 equivalents, more preferably 4 to 6 equivalents, based on the equivalent of the compound of formula I-3.

In the method for preparing the compound of formula (I-4), the reaction temperature is preferably about 0 to 40 ℃, more preferably 15 to 30 ℃. The reaction solvent is preferably selected from methylene chloride, THF, chloroform and dichloroethane.

The present invention provides a pharmaceutical composition for preventing or treating cardiovascular disease, comprising a compound represented by Formula A or a pharmaceutically acceptable salt thereof:

(A)

In this formula,

X is -CH- or nitrogen;

Y is —CH ₂ —, —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ —O— or —O—CH ₂ —;

R _m is a hydrogen atom, an acetyl group, a tri (C1-C4) alkylsilaneyl group, a diarylboranyl group or a (t-butoxy) carbamyl group;

R _n is a hydrogen atom or a C1-C4 alkyl group;

R _o , R _p or R _q are each a hydrogen atom, a hydroxyl group, a halogen atom, a (C6-C10) aryl group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy group, a tri (C1-C4) alkylsilane Oxy group or benzodioxylyl group;

R _o And R _p Or R _p And R _q together are —CH ₂ —CH═CH—, —CH═CH—CH═CH—,

-CH = CH-CH = CH-CH _2- .

The compound represented by the formula A is preferably X is -CH- or nitrogen; Y is —CH ₂ —, —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ —O— or —O—CH ₂ —; R _m And R _n is a hydrogen atom; R _o , R _p or R _q are each a hydrogen atom, a hydroxyl group, a halogen atom, a (C6-C10) aryl group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy group, a tri (C1-C4) alkylsilane Oxy group or benzodioxylyl group; R _o And R _p Or R _p And R _q may together be —CH ₂ —CH═CH— or —CH═CH—CH═CH—.

The compound represented by Formula A may preferably be a trans or cis isomer when X is -CH = CH-, and more preferably, a trans isomer.

The compound represented by Formula A may be a compound selected from the compounds listed below:

3-benzyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (o-bromobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (p-methoxybenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3-phenethyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (p-chlorobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (phenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (naphthalen-3-yloxy) methyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3-((4-chlorophenoxy) methyl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3-((2,4-dichlorophenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

1- (pyridin-2-yl) -3-styryl-1H-pyrazol-5-ol,

3- (4-methoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3,4-dimethoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3,4-dichlorostyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4- i -propylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4-trifluoromethylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (3-methoxy-4-t-butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (3,5-dimethoxy-4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (3-methoxy-4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol,

3- (4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3,5-dimethoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol,

4-((E) -2- (5-amino-1- (pyridin-2-yl) -1H-pyrazol-3-yl) vinyl) -2-methoxyphenol.

More preferably, the compound of formula A of the present invention is selected from the compounds listed below and their pharmaceutically acceptable salts:

3-phenethyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (p-chlorobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5ol,

3- (phenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (naphthalen-3-yloxy) methyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3-((2,4-dichlorophenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

1- (pyridin-2-yl) -3-styryl-1H-pyrazol-5-ol,

3- (4-methoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3,4-dimethoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (3,4-dichlorostyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4-trifluoromethylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol,

3- (4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol,

3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol.

Meanwhile, the compound represented by Chemical Formula A or a pharmaceutically acceptable salt thereof may be prepared by a method of preparing the compound of Chemical Formula A by heating a compound of Chemical Formula B and 2-hydrazinopyridine in a polar organic solvent and heating the same. .

[Formula B]

(A)

Wherein X is -CH-;

Y is —CH ₂ —, —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ —O— or —O—CH ₂ —;

R _m is a hydrogen atom, an acetyl group, a tri (C1-C4) alkylsilaneyl group, a diarylboranyl group or a (t-butoxy) carbamyl group;

R _n is a hydrogen atom or a C1-C4 alkyl group;

R _o , R _p or R _q are each a hydrogen atom, a hydroxyl group, a halogen atom, a (C6-C10) aryl group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy group, a tri (C1-C4) alkylsilane Oxy group or benzodioxylyl group;

R _o And R _p Or R _p And R _q together are —CH ₂ —CH═CH—, —CH═CH—CH═CH—,

-CH = CH-CH = CH-CH _2- .

X is -CH- or nitrogen; Y is —CH ₂ —, —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ —O— or —O—CH ₂ —; R _m and R _n are hydrogen atoms; R _o , R _p or R _q are each a hydrogen atom, a hydroxyl group, a halogen atom, a (C6-C10) aryl group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy group, a tri (C1-C4) alkylsilane Oxy group or benzodioxylyl group; R _o And R _p Or R _p And it is more preferred to prepare compounds of formula A wherein R _q together are —CH ₂ —CH═CH— or —CH═CH—CH═CH—.

The β-keto ester, which is a compound of formula B, used as starting material may be commercially available. Or when Y is —CH ₂ —, —CH ₂ CH ₂ —, —CH ₂ —O— or —O—CH ₂ —. Chem., Vol. 43, No. 10, 1978, 2087-2088. Specifically, the product produced by reacting a commercially available acyl chloride derivative with Meldrum's acid may be prepared by heating and refluxing in an ethanol solvent. Can be. When Y is -CH = CH-, the cinnamic acid derivative is reacted with carbonyldiimidazole (CDI) to activate the acid site of the cinnamic acid derivative with acyl imidazole, and then lithium bis (trimethylsilyl) It can be prepared by reacting with either ethyl acetate or ethylthioacetate in the presence of amide (LiHMDS).

2-hydrazinopyridine is preferably used in an amount of 1.0 to 3 molar equivalents relative to the molar amount of compound II.

The polar organic solvent is preferably selected from C1-C4 alcohols such as methanol, ethanol, n-propanol, i-isopropanol, n-butanol, t-butanol, acetic acid and mixtures thereof. More preferred is ethanol or acetic acid.

The heating is preferably at a temperature at which the solvent can be refluxed, preferably at about 100 to about 130 ° C.

The reaction time is preferably carried out for 2 to 72 hours.

The present invention also provides a composition for preventing or treating cardiovascular disease, comprising a compound selected from the compounds listed below and pharmaceutically acceptable salts thereof:

1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol (211);

1- (pyridin-2-yl) -3-phenyl-4-benzyl- 1H -pyrazol-5-ol 212;

1- (pyridin-2-yl) -3-phenyl-4- (4-nitrobenzyl) 1H -pyrazol-5-ol (225);

Hydrochloride 278 of 1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol;

1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -5 (isopropyloxycarbonyloxymethyloxy) pyrazole 306;

Hydrochloride 308 of 1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E -ethenyl] -4-benzyl- 1H -pyrazole-5-ol;

1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E-ethenyl] -4-benzyl-5-hydroxypyrazole 274;

3- (4-nitrophenyl) -3- [2- (pyrimidin-2-yl) hydrazono] propionic acid ethyl ester;

1- (pyrimidin-2-yl) -3- (4-nitrophenyl) -5-1H -pyrazole-5-ol (105);

1- (pyridin-2-yl) -3- (1,2-diphenyl-butenyl -E-) - 1H - pyrazol-5-ol (263);

Hydrochloride 305 of 1- (pyridin-2-yl) -3-phenyl- 1H -pyrazole-5-ol;

3- (4-methoxy-phenylamino) - 1H - pyrazol-5-ol (15);

4-hexylidene-1-phenyl-3- (pyridin-2-yl) - 1H - pyrazol-5-ol (213);

1- (pyridin-2-yl) -3- (3- (trifluoromethyl) phenyl) -1H-pyrazol-5-ol;

1- (pyridin-2-yl) -3- (4- (trifluoromethyl) phenyl) -1H-pyrazol-5-ol;

3- (3-nitrophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

1- (pyridin-2-yl) -3- (3,4,5-trimethoxyphenyl) -1H-pyrazol-5-ol;

3- (2-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (2-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (2-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4-iodophenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol;

2- (3- (4-iodophenyl) -5- (triisopropylsilyloxy) -1H-pyrazol-1-yl) pyridine;

3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

t-butyl 3- (2-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (3-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (4-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (4-iodophenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl carbonate;

3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl acetate;

3- (biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

t-butyl 3- (4- (naphthalene) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (3 '-(dimethylamino) biphenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

3- (2- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (3'-phenylbiphenyl-2-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (4 '-(benzyloxy) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (4'-bromobiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

t-butyl 3- (3'-formylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (2'-phenoxybiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

3- (3- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (3'-phenylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

t-butyl 3- (3- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (3 '-(dimethylamino) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

t-butyl 3- (4'-methoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

3- (4 '-(benzyloxy) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (4'-bromobiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (3'-formylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

t-butyl 3- (2'-phenoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;

3- (biphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

3- (3'-phenylbiphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;

2- (3- (4'-bromobiphenyl-4-yl) -5- (triisopropylsilyloxy) -1H-pyrazol-1-yl) pyridine;

2- (3- (biphenyl-4-yl) -5- (diphenylboryloxy) -1H-pyrazol-1-yl) pyridine;

3- (biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3 '-(dimethylamino) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (2- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3'-phenylbiphenyl-2-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4 '-(benzyloxy) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4'-bromobiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3'-formylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (2'-phenoxybiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3'-phenylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3 '-(dimethylamino) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4'-methoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4 '-(benzyloxy) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4'-bromobiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3'-formylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (2'-phenoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (biphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol;

3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol;

3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3-phenyl-4-propyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;

4-benzyl-3-phenyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3-benzyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (o-bromobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (p-methoxybenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3-phenethyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (p-chlorobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (phenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (naphthalen-3-yloxy) methyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3-((4-chlorophenoxy) methyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3-((2,4-dichlorophenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

1- (pyridin-2-yl) -3-styryl-1H-pyrazol-5-ol;

3- (4-methoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3,4-dimethoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3,4-dichlorostyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4- i -propylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4-trifluoromethylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol;

3- (3-methoxy-4-t-butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol;

3- (3,5-dimethoxy-4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol;

3- (3-methoxy-4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol;

3- (4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3,5-dimethoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;

3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol; And

4-((E) -2- (5-amino-1- (pyridin-2-yl) -1H-pyrazol-3-yl) vinyl) -2-methoxyphenol.

In the present invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, tartaric acid and sulfuric acid, Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid Sulfonic acid salts prepared with organic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like. And the like, and the salts used in the present invention are not limited by the salts listed. Preferably the pharmaceutically acceptable salt may be a hydrochloride salt.

The composition of the present invention not only effectively inhibits the movement of smooth muscle cells, but also inhibits the production of free radicals, and can be usefully used for the treatment of cardiovascular diseases such as atherosclerosis and vascular restenosis. Furthermore, the composition of the present invention exhibits a similar effect of treating cardiovascular diseases as existing pyrazole derivatives (see Patent No. 00-0987557), which has been proven to treat atherosclerosis. The stability is very good, there is an advantage that can treat cardiovascular disease without side effects.

Therefore, the composition of the present invention is useful for the treatment of cardiovascular diseases, and particularly effective in the prevention and treatment of vascular restenosis. That is, the composition of the present invention can be used for the purpose of preventing and treating coronary stenosis causing angina or myocardial infarction, and to prevent the restenosis frequently occurring after percutaneous coronary angioplasty performed for the purpose of treating coronary stenosis. It can also be used for the purpose. Examples of percutaneous coronary angioplasty include balloon angioplasty, stent insertion, coronary artery bypass surgery, and arterial-venous anastomosis. One example of use of the pharmaceutical composition according to the present invention is to administer it in the same way as a general medicine or to apply it to a stent. It is preferably used in sustained release drug stents.

In the present invention, "cardiovascular disease" as the cardiovascular disease is a disease including heart disease, such as heart failure, hypertensive heart disease, arrhythmia, congenital heart disease, myocardial infarction and angina, and vascular diseases such as stroke and peripheral vascular disease And, broadly, ischemic cardiovascular disease, and especially arteriosclerosis or vascular restenosis.

The composition of the present invention may include additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusting agents, antioxidants, dissolution aids and the like within the scope of not impairing the effects of the present invention.

The diluent may be sugar, starch, microcrystalline cellulose, lactose (lactose monohydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or a mixture thereof; Binders are starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose monohydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose , Hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof.

The disintegrating agent may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

Lubricants include talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, mixtures thereof, and the like.

pH adjusters include acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium ether, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, ammonia water, meglumine, carbonate Basic agents, such as sodium, magnesium oxide, magnesium carbonate, sodium citrate, and calcium tribasic phosphate, etc. can be used.

The antioxidant may be dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, etc. In the pre-release compartment of the present invention, the dissolution aid is Polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, sodium docusate, poloxamer and the like.

In addition, an enteric polymer, a water-insoluble polymer, a hydrophobic compound, and a hydrophilic polymer may be included to form a delayed-release preparation.

The enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher, and for example, hypromellose acetate succinate, hypromellose phthalate (hydrate Hydroxypropylmethyl cellulose phthalate), hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethyl ethyl cellulose and ethyl hydrate Enteric cellulose derivatives such as oxyethyl cellulose phthalate and methyl hydroxyethyl cellulose; Styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylic acid copolymers (e.g., acrylics), butyl acrylate-styrene-acrylic acid copolymers, and methyl acrylate-methacrylic acid-octyl acrylate copolymers. The enteric acrylic acid copolymer; Poly (methacrylate methyl methacrylate) copolymer (e.g. Eudragit L, Eudragit S, Evonik, Germany), poly (methacrylate acrylate) copolymer (e.g. Eudragit L100- Enteric polymethacrylate copolymers such as 55); Vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinylbutyl ether-maleic anhydride copolymer, acrylic Enteric maleic acid copolymers such as ronitrile-methyl methacrylate-maleic anhydride copolymer and butyl styrene-styrene-maleic anhydride copolymer; And enteric polyvinyl derivatives such as polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate.

The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. For example, the water insoluble polymer may be polyvinylacetate (e.g. colicoat SR30D), water insoluble polymethacrylate copolymer [e.g. poly (ethylacrylate-methyl methacrylate) copolymer (e.g. Eudragit NE30D) , Poly (ethylacrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer (e.g., Eudragit RSPO), etc., ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose roacylate , Cellulose rotriacrylate, cellulose acetate, cellulose diacetate and cellulose triacetate.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. Fatty acids and fatty acid esters such as, for example, glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and threric acid; Fatty acid alcohols such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; Waxes such as carnauba wax, beeswax, and microcrystalline wax; Inorganic materials such as talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and gum.

The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. Sugars such as, for example, dextrins, polydextrins, dextrans, pectins and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactans, starches, hydroxypropylstarches, amylose, and amylopectins ; Cellulose derivatives such as hypromellose, hydroxypropyl cellulose , hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose and carboxymethyl cellulose sodium; Gums such as guar gum, locust bean gum, tragacantha, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum; Proteins such as gelatin, casein, and zein; Polyvinyl derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate; Poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit E100, Evonik, Germany), poly (ethyl acrylate-methyl methacrylate- Hydrophilic polymethacrylate copolymers such as triethylaminoethyl- methacrylate chloride) copolymers (eg, Eudragit RL, RS, Evonik, Germany); Polyethylene derivatives such as polyethylene glycol, and polyethylene oxide; Carbomer and the like.

In addition, a pharmaceutically acceptable additive may be selected and used in the preparation of the present invention as various additives selected from colorants and fragrances.

In the present invention, the range of the additives is not limited to the use of the above additives, and the above-mentioned additives may be formulated by containing a dose in a normal range by selection.

The pharmaceutical compositions according to the invention can be used in the form of oral dosage forms, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories or sterile injectable solutions according to conventional methods. have.

The present invention also provides a method for preventing cardiovascular disease by administering to a subject comprising a mammal a composition comprising a compound represented by Formula 1, Formula I, or Formula A of the present invention, a compound recited above, or a pharmaceutically acceptable salt thereof Or a method of treatment. As used herein, the term "administration" means introducing a composition for preventing and treating cardiovascular diseases of the present invention to a patient by any suitable method, and the route of administration of the composition for preventing and treating cardiovascular diseases of the present invention reaches a target tissue. As far as possible, administration may be via any general route. Oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, endothelial administration, intranasal administration, intrapulmonary administration, rectal administration, intranasal administration, intraperitoneal administration, intradural administration, but is not limited thereto.

The composition for preventing or treating cardiovascular diseases according to the present invention may be administered once or twice a day at regular time intervals.

The dosage of the compound represented by Formula 1, Formula I or Formula A, the above-listed compound or a pharmaceutically acceptable salt thereof may be determined by the weight, age, sex, health condition, diet, time of administration, method of administration, The range varies depending on the rate of excretion and the severity of the disease. 0.1 to 100 mg / kg / day, more preferably 10 to 40 mg / kg / day, but this may vary depending on the severity, age, sex and the like of the patient.

The present invention also provides a drug delivery device for topical administration of a composition comprising a compound of Formula 1, Formula I or Formula A, for treating or preventing vascular restenosis. The drug delivery device for topical administration is preferably an implantable stent to which the composition of the present invention is applied.

In the present invention, stent means a general apparatus for endoluminal appilcation, for example, a blood vessel, as mentioned above, and the disease occurs in a place where blood flow should be smooth. Refers to a cylindrical medical material that normalizes blood flow by inserting into narrowed or clogged blood vessels under x-ray without surgically open surgery. For example, vascular stents are described by Eric J Topol in "Textbook of Interventional Cardiology", Saunders Company, 1994. Preferably, it is a sustained release drug-eluting stent.

As a specific example, in order to produce a stent according to the present invention, the composition may be coated on the stent.

As a method of coating the composition on the stent, a conventional coating method known to those skilled in the art may be applied, for example, a dip-coated coating and a polymer together with a polymer. There is a method of coating, and the dip coating method is the simplest coating method, and since only the pharmaceutical composition is coated, it is easy to observe the biological effect of the drug but is not limited thereto. Preferably, the stent of the present invention may be prepared by mixing the composition with a polymeric material in a drug-release stent so as to slowly release the composition according to the present invention. Polymeric materials that can be used in drug release stents are well known in the art and include, for example, polyurethanes, polyethylene terephthalates, PLLA-poly-glycolic acid copolymers (PLGA), polycaprolactones, poly- (hydrides) Oxybutyrate / hydroxyvalerate) copolymer, polyvinylpyrrolidone, polytetrafluoroethylene, poly (2- hydroxyethylmethacrylate), poly (etheruretan urea), silicone, acrylic, epoxide, Polyesters, urethanes, palene, polyphosphazine polymers, fluoropolymers, polyamides and polyolefins, but are not limited thereto.

The present invention also provides a method of eliminating vascular narrowing by administering to a subject a composition comprising a compound of Formula 1, Formula I or Formula A.

The method for removing vascular stenosis of the present invention includes administering a composition comprising a compound of Formula 1, Formula I, or Formula A in a pharmaceutically effective amount. It will be apparent to those skilled in the art that a suitable total daily dose may be determined by the practitioner within the correct medical judgment. The specific therapeutically effective amount for a particular patient may be based on the specific composition, including the type and severity of the reaction to be achieved, whether or not other agents are used in some cases, the age, weight, general health, sex and diet of the patient, time of administration, Different applications are desired depending on the route of administration and the rate of release of the composition, the duration of treatment, the drug used in conjunction with or concurrently with the specific composition and similar factors well known in the medical arts.

In one preferred embodiment of the invention, the treatment methods of the invention may comprise administering one or more known therapeutic agents in combination with a pharmaceutical composition comprising a compound of Formula 1, Formula I or Formula A.

Known therapeutic agents can be exemplified by paclitaxel or silorimus, and the pharmaceutically effective amounts of the known therapeutic agents are known in the art and include the degree of symptoms, the co-administration with the composition of the present invention, and the like. Considering all the conditions, the treating physician can adjust the amount. As a result of concurrently administering a known therapeutic agent, the composition of the present invention can not only reduce side effects and the like of the known therapeutic agent but also expect a synergistic therapeutic effect with the family. These known therapeutic agents may optionally be administered in combination or simultaneously, or at intervals of time with the compositions of the invention.

The compound of the present invention is excellent in active oxygen production inhibitory activity and can be used for treating or preventing cardiovascular diseases without any special side effects such as conventional therapeutic agents.

1 is a diagram observing the degree of smooth muscle cell migration by the experimental group and the control group under a microscope.
Figure 2 shows a graph comparing the degree of smooth muscle cell migration by the experimental group and the control group.
3 is a diagram illustrating a human aortic smooth muscle cell treated with an experimental group and a control group using a confocal microscope.
4 is a graph showing the relative fluorescence intensity of the human aortic smooth muscle cells treated with the experimental group and the control group.
5 to 10 are graphs showing the relative superoxide generation values of the experimental and control groups in the Nox1 / Nox2 / Nox3 / Nox4 / Duox1 / Duox2 membrane, respectively.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. These Examples and Experimental Examples are only for illustrating the present invention, and the scope of the present invention is not limited to the following Examples and Experimental Examples.

In addition, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea, Alfa Aesar, or Tokyo Chemical Industry (TCI), unless otherwise noted, and ¹ H-NMR data measured by JEOL's Eclipse FT 300 MHz Spectrometer. ¹³ C-NMR data is measured by the Eclipse FT 300 MHz Spectrometer of JEOL, Mass data is measured by JEOL MStation JMS 700 mass Spectrometer.

V) m / z (rel intensity) 279 (M +, 37), 250 (100).

Example  1: 1- (pyridin-2-yl) -3- Phenyl -4-propyl- 1H - Pyrazole -5-All? HCl Synthesis of (278)

...[화학식 1-1]

... [Formula 1-1]

280 mg of 1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol prepared in Example 1 was dissolved in 4 mL of ethyl ether in a round bottom flask. 0.55 mL of ethyl ether in which 2 M HCl was dissolved was slowly added dropwise at 0 ° C. The solid produced in the reaction solution was filtered under reduced pressure to remove the solvent, washed with hexane and ethyl acetate and dried in vacuo to give 270 mg of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.44 (1H, d, J = 4.2 Hz), 8.08-8.03 (2H, m), 7.66-7.64 (2H, m), 7.48-7.42 (3H, m ), 7.34-7.30 (1H, m), 2.49 (2H, brs), 2.43 (2H, t, J = 7.5 Hz), 1.48 (2H, m), 0.48 (3H, t, J = 7.3 Hz).

Example  2: 1- (pyridin-2-yl) -3- Phenyl - 1H - Pyrazole -5-All? HCl Synthesis of Phosphorus (305)

...[화학식 1-2]

[Formula 1-2]

Ethyl benzoyl acetate (1.92 g, 9.99 mmol) and 10 ml of ethanol were added to a round bottom flask, and 2-hydrazinopyridine (1.1 g, 10.0 mmol) was diluted in 10 ml of ethanol and slowly added dropwise at 0 ° C. The reaction solution was heated to reflux at 100 ° C. for 8 hours. The reaction was distilled under reduced pressure to remove the solvent, and then the resulting solid was washed with hexane and ethyl acetate and dried in vacuo to give 1- (pyridin-2-yl) -3-phenyl- 1H -pyrazole-5-ol in 87% yield. Obtained.

Into a round bottom flask, 4 mL of ethyl ether was added to 237 mg of 1- (pyridin-2-yl) -3-phenyl- 1H -pyrazol-5-ol prepared above, and 0.55 mL of ethyl ether dissolved in 2M HCl. Was slowly added dropwise at 0 ° C. The solid produced in the reaction solution was filtered under reduced pressure to remove the solvent, washed with hexane and ethyl acetate and then dried in vacuo to give the title compound in 87% yield.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.48-8.46 (m, 1H), 8.08 (t, 1H, J = 8.3 Hz), 7.96 (d, 1H, J = 8.4 Hz), 7.87 (d, 2H, J = 8.3 Hz), 7.46-7.35 (m, 4H), 6.64 (br, 4H), 6.14 (s, 1H).

Example  3: 1- (pyridin-2-yl) -3- Phenyl -4-propyl- 1H -5- ( Isopropyloxycarbonyloxymethyloxy ) Pyrazole  Synthesis (306)

...[화학식 1-3]

[Formula 1-3]

438 mg of 1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol prepared in Example 1 in a mixed solvent of 8 mL of water and 8 mL of dichloromethane, K ₂ CO After adding ₃ 650 mg, 532 mg of Bu ₄ NHSO ₄ , a solution of 497 mg of isopropyloxycarbonyloxymethyliodide in 2 mL of dichloromethane was added. Thereafter, the solution was stirred vigorously overnight to react the compounds. The organic layer obtained by extracting the reaction with dichloromethane was washed with water and brine, and the concentrated residue was purified by column chromatography (developing solvent: hexane / ethyl acetate (EtOAc = 10/1) to obtain the title compound (361 mg). , Yield 58%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48-8.46 (1H, m), 7.89 (1H, d, J = 8.2 Hz), 7.80 (1H, m), 7.78-7.68 (2H, m), 7.57- 7.34 (3H, m), 7.23-7.16 (1H, m), 5.84 (2H, s), 4.86 (1H, m), 2.55 (2H, d, J = 7.7 Hz), 1.58 (2H, m), 1.25 (6H, d, J = 6.3 Hz), 0.91 (3H, t, J = 7.5 Hz)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 153.6, 152.0, 150.8, 149.3, 147.9, 138.3, 134.0, 128.4, 128.0, 127.6, 121.3, 115.9, 110.0, 92.6, 72.7, 24.7, 22.9, 21.6, 14.1.

Example  4: 1- (pyridin-2-yl) -3-[(3- Methoxy -4- Hydroxyphenyl ) - E - Ethenyl ] -4-benzyl- 1H - Pyrazole -5-All? HCl Synthesis of (308)

...[화학식 1-4]

... [Formula 1-4]

To a round bottom flask, 2-benzyl-3-oxo-3-[(3-methoxy-4-hydroxyphenyl) -E -ethenyl] propionic acid ethyl ester (3.55 g, 10 mmo) and 10 mL of acetic acid were added. To this was diluted 2-hydrazinopyridine (1.1 g, 10.1 mmol) in 3 mL of acetic acid and slowly added dropwise at 0 ° C. The reaction solution was heated to reflux at 100 ° C. for 2 days. The reaction product was distilled under reduced pressure to remove the solvent, and the residue was then purified by column chromatography (developing solvent: hexane / ethyl acetate (EtOAc) = 15/1) to give 1- (pyridin-2-yl) -3-[(3 1.32 g of -methoxy-4-hydroxyphenyl) -E -ethenyl] -4-benzyl- 1H -pyrazole-5-ol was obtained.

In a round bottom flask, 1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E -ethenyl] -4-benzyl- 1H -pyrazole-5 obtained above. 1.10 g of -ol was dissolved in 15 mL of ethyl ether. 1.5 mL of ethyl ether in which 2 M HCl was dissolved was slowly added dropwise at 0 ° C. After stirring at 40 ° C. for 24 hours, the solid produced in the reaction solution was filtered under reduced pressure to remove the solvent, washed with hexane and ethyl acetate and dried in vacuo to yield 1.1 g of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.47-8.45 (1H, m), 8.30 (1H, d, J = 8.4 Hz), 7.98-7.93 (2H, m), 7.32-6.83 (10H, m ), 3.82 (3H, s), 2.72 (2H, s).

Comparative example  1: 3- Phenyl -1- (pyridin-2-yl) -1H- Pyrazole Synthesis of -5-ol (89403)

[화학식 5]

[Chemical Formula 5]

The 3-phenyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol was synthesized using the method disclosed in Korean Patent No. KR 0942382.

Ethyl benzoyl acetate (1 equivalent) and 4 ml of ethanol were added to a round bottom flask, and 2-hydrazinopyridine (1.1 equivalent) was diluted in 3 ml of ethanol and slowly added dropwise at 0 ° C. Heated to reflux for 20 minutes. After distillation under reduced pressure to remove the solvent, the resulting solid was washed with hexane and ethyl acetate and dried in vacuo to give the title compound in a yield of 87%.

< Experimental Example  1> Smooth muscle cell ( Smooth Muscle Cell ) Confirmation of movement inhibitory effect

In order to examine the effect of the compounds of the present invention on the movement of smooth muscle cells (SMC), human aortic smooth muscle cells (Human aortic smooth muscle cells) after the LPS stimulation of the movement of the cells using a Transwell system It was measured by. At this time, the group synthesized with the compounds (Examples 1 ( 278 ), 2 ( 305 ), 3 ( 306 ) and 4 ( 308 )) synthesized in the above example to smooth muscle cells as a test group, smooth muscle as a control group A group in which the compound of Comparative Example 1 ( 89403 ) was added to the cells at the same concentration as the compound of the above Example, or a group without LPS stimulation without adding the compound synthesized in the Example or Comparative Example ( (-) LPS ) and the example or Comparative without addition of the compound synthesized in example without LPS stimulation were compared to standard group ((+) LPS).

Specifically, the membrane was coated with fibronectin under the upper layer of the transwell (Costar Corning, Cambridge, MA), and then plated with human aortic smooth muscle cells (8X10 ³ ) in the upper chamber of the transwell. . The upper chamber was pre-incubated for 30 minutes in a plate containing the following compound, followed by incubation for 16 hours.

Subsequently, human aortic smooth muscle cells (Human aortic smooth muscle cells) moved through the transwell were fixed in 70% methanol for 1 minute, hematoxylin for 5 minutes, and eosin for 2 minutes. After removing the human aortic smooth muscle cells that remained in the chamber without moving, only the human aortic smooth muscle cells that migrated were observed under a microscope (Fig. 1) and counted. The degree of cell migration was compared (FIG. 2).

As can be found in FIG. 1 and 2, the test group it can be seen that it has effectively inhibits the migration of vascular smooth muscle cells as compared to a group of ((+) LPS) received only LPS. Therefore, the composition containing the pyrazole derivatives of the present invention effectively inhibits the movement of vascular smooth muscle cells, it can be seen that there is a therapeutic department for cardiovascular diseases such as prevention of vascular restenosis, arteriosclerosis.

< Experimental Example  2> free radicals ROS To inhibit the formation of Confocal  microscope( confocal microscope )

Human aortic smooth muscle cells (2X10 ⁵ ) were plated in a 35 mm dish and cultured for one day. Serum starvation was carried out for 16 hours, classified into 7 groups of samples, and pre-incubated with each compound for 30 minutes, and then treated with LPS for 20 minutes.

Then, argon laser (excitation wavelength: 488nm, emission filter: 515) of confocal microscope (LSM510, Version 2.3) was stained with 10uM DCF-DA (2 ', 7'-dichlorodihydrofluorescein diacetate) for 10 minutes in the dark. to 540 nm) was observed (FIG. 3).

Five pictures were taken from each sample, and the fluorescence intensity was measured by Zeiss vision system (LSM510, Version 2.3). The relative fluorescence intensity value was calculated based on the DMSO control value by substituting the obtained intensity value into the following equation, and the result is shown in FIG. 4.

Incubate the human aortic smooth muscle cell (2X10 ⁵ ) in a 35mm dish for one day. After 16 hours of starvation in a serum-free media, 20 minutes of stimulation with 100ug / ml LPS was performed, followed by staining with 10uM DCF-DA (2 ', 7'-dichlorodihydrofluorescein diacetate) for 10 minutes in the dark and confocal microscope (LSM510, Version 2.3). Observe the image using an argon laser (excitation wavelength: 488nm, emission filter: 515 to 540nm). Five photographs were taken from each sample and the fluorescence intensity was measured by Zeiss vision system (LSM510, Version 2.3). Each intensity value is converted into a relative fluorescence intensity value based on the DMSO control value.

As can be seen in Figure 3 and Figure 4, the experimental group was reduced relative fluorescence intensity compared to the control group administered only LPS, the experimental group and the control group proved to be effective atherosclerosis (Registered Patent No. 1-0987557) Similar fluorescence intensity values were shown. Therefore, the composition containing the pyrazole derivatives of the present invention efficiently inhibits the production of free radicals (ROS), it can be seen that there is a therapeutic department for cardiovascular diseases such as vascular restenosis prevention, arteriosclerosis.

< Experimental Example  3> free radicals ROS To inhibit the formation of Lucigenin  Based analytics ( lucigenin based assay )

(1) the plasma membrane of fruit flies ( plasma membrane )

Plasma membranes were isolated from transgenic Drosophila overexpressing Human Nox1 / Nox2 / Nox3 / Nox4 / Duox1 / Duox2 as follows.

Drosophila was placed in PBS buffer and the tissue was crushed with a homogener, sonicated, and centrifuged at 10000 g for 3 minutes. After taking the supernatant, the pellet was obtained by centrifugation at 4 ° C. and 100000 g for 1 hour, and the pellet was resuspended in PBS to obtain each Nox1 / Nox2 / Nox3 / Nox4 / Duox1 / Duox2 Nox enzyme. .

(2) superoxide ( superoxide ) Production measurement

Compounds synthesized in the above Examples as the experimental group on the Nox1 membrane obtained in (1) (Examples 1 ( 278 ), 2 ( 305 ), 3 ( 306 ) and 4 ( 308 )), the compound of Comparative Example 1 as a control ( 89403) and DMSO control, respectively, by concentration, while adding 500uM NADH and 500uM lucigenin together, the excess oxide produced at 28 degrees for 15 minutes with Multimode dectector (DTX 880, Beckman coulter) superoxide) was measured.

The relative superoxide generation value was calculated by substituting the amount of superoxide into the following equation, and the result is shown in FIG. 5.

Also, for each Nox2 / Nox3 / Nox4 / Duox1 / Duox2 membrane obtained in the above (1), the amount of superoxide was measured in the same manner as above, and the relative superoxide generation value was calculated. 6 to 10 are shown.

As can be seen in Figures 5 to 10, for all the Nox1 / Nox2 / Nox3 / Nox4 / Duox1 / Duox2 membrane in which the experiment was performed, the control group proved the effect of treating arteriosclerosis in all experimental groups (registered patent No. 1-0987557) Relative superoxide generation is similar to that of Ho.

Therefore, the composition containing the pyrazole derivatives of the present invention efficiently inhibits the production of free radicals (ROS), it can be seen that there is a therapeutic department for cardiovascular diseases such as vascular restenosis prevention, arteriosclerosis.

Claims (8)

A composition for preventing or treating cardiovascular diseases comprising a compound represented by the following Formula 1:
[Formula 1]

In this formula,
X is -CH- or nitrogen;
R ₁ is a hydrogen atom or isopropyloxycarbonyloxymethyl;
R ₂ is a hydrogen atom, straight or branched chain alkyl of C 1 to C 4, substituted or unsubstituted benzyl; And
R ₃ is phenyl, nitrophenyl, substituted or unsubstituted phenylethenyl or substituted or unsubstituted diphenylethenyl;
Wherein if X is -CH- and R ₁ and R ₂ are hydrogen atoms, then R ₃ is substituted or unsubstituted diphenylethenyl, or if X is a nitrogen atom and R ₁ and R ₂ are hydrogen atoms, then R ₃ is Substituted or nitrophenyl or unsubstituted diphenylethenyl,
The substituent is nitro, hydroxy or methoxy. A composition for preventing or treating cardiovascular disease, including a pharmaceutically acceptable salt of a compound represented by Formula 1 below:
[Formula 1]

In this formula,
X is -CH- or nitrogen;
R ₁ is a hydrogen atom or isopropyloxycarbonyloxymethyl;
R ₂ is a hydrogen atom, straight or branched chain alkyl of C 1 to C 4, substituted or unsubstituted benzyl; And
R ₃ is phenyl, nitrophenyl, substituted or unsubstituted phenylethenyl or substituted or unsubstituted diphenylethenyl;
Wherein if R ₁ and R ₂ are hydrogen atoms, R ₃ is phenyl, nitrophenyl or substituted or unsubstituted diphenylethenyl,
The substituent is nitro, hydroxy or methoxy. A pharmaceutical composition for preventing or treating cardiovascular disease, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:
(I)

Wherein X is -CH- or nitrogen;
R _a is a hydrogen atom, an acetyl group, a tri (C 1 -C 4) alkylsilaneyl group, a diphenylboranyl group or a (t-butoxy) carbonyl group;
R _b , R _c or R _d are each a hydrogen atom, a halogen atom, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy group, a benzo [d] [1,3] dioxol group, a substituted or unsubstituted ratio Phenyl group or substituted or unsubstituted (C6-C10) aryl group, wherein the substituent is a halogen atom, (C1-C4) alkyl amine group, halo (C1-C3) alkyl group, (C1-C6) alkoxy, phenoxy group, benzyl A phenyl group substituted with an oxy group, formyl group or halogen atom, but R _b , R _c and R _d are not all hydrogen atoms. A pharmaceutical composition for preventing or treating cardiovascular disease, comprising a compound of Formula A or a pharmaceutically acceptable salt thereof:
[Formula A]

Wherein X is -CH- or nitrogen;
Y is -CH _2- , -CH ₂ CH _2- , -CH = CH-, -CH ₂ -O-or -O-CH _2- ;
R _m is a hydrogen atom, an acetyl group, a tri (C 1 -C 4) alkylsilaneyl group, a diarylboranyl group or a (t-butoxy) carbamyl group;
R _n is a hydrogen atom or a C1-C4 alkyl group;
R _o , R _p or R _q are each a hydrogen atom, a hydroxyl group, a halogen atom, a (C6-C10) aryl group, a halo (C1-C3) alkyl group, a (C1-C6) alkoxy group, a tri (C1-C4) alkylsilane An oxy or benzodioxylyl group;
R _o And R _p Or R _p And R _q together are —CH ₂ —CH═CH—, —CH═CH—CH═CH—,
-CH = CH-CH = CH-CH _2- . A composition for preventing or treating cardiovascular disease, comprising at least one compound selected from the group consisting of the compounds listed below and their pharmaceutically acceptable salts.
1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol (211);
1- (pyridin-2-yl) -3-phenyl-4-benzyl- 1H -pyrazol-5-ol 212;
1- (pyridin-2-yl) -3-phenyl-4- (4-nitrobenzyl) 1H -pyrazol-5-ol (225);
Hydrochloride 278 of 1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol;
1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -5 (isopropyloxycarbonyloxymethyloxy) pyrazole 306;
Hydrochloride 308 of 1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E -ethenyl] -4-benzyl- 1H -pyrazole-5-ol;
1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E-ethenyl] -4-benzyl-5-hydroxypyrazole 274;
3- (4-nitrophenyl) -3- [2- (pyrimidin-2-yl) hydrazono] propionic acid ethyl ester;
1- (pyrimidin-2-yl) -3- (4-nitrophenyl) -5-1H -pyrazole-5-ol (105);
1- (pyridin-2-yl) -3- (1,2-diphenyl-butenyl -E-) - 1H - pyrazol-5-ol (263);
Hydrochloride 305 of 1- (pyridin-2-yl) -3-phenyl- 1H -pyrazole-5-ol;
3- (4-methoxy-phenylamino) - 1H - pyrazol-5-ol (15);
4-hexylidene-1-phenyl-3- (pyridin-2-yl) - 1H - pyrazol-5-ol (213);
1- (pyridin-2-yl) -3- (3- (trifluoromethyl) phenyl) -1H-pyrazol-5-ol;
1- (pyridin-2-yl) -3- (4- (trifluoromethyl) phenyl) -1H-pyrazol-5-ol;
3- (3-nitrophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-nitrophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-methoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3,4-dimethoxyphenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
1- (pyridin-2-yl) -3- (3,4,5-trimethoxyphenyl) -1H-pyrazol-5-ol;
3- (2-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-fluorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (2-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-chlorophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (2-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-iodophenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol;
2- (3- (4-iodophenyl) -5- (triisopropylsilyloxy) -1H-pyrazol-1-yl) pyridine;
3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
t-butyl 3- (2-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (3-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (4-iodophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (4-iodophenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl carbonate;
3- (4-bromophenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl acetate;
3- (biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
t-butyl 3- (4- (naphthalene) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (3 '-(dimethylamino) biphenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
3- (2- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (3'-phenylbiphenyl-2-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (4 '-(benzyloxy) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (4'-bromobiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
t-butyl 3- (3'-formylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (2'-phenoxybiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
3- (3- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (3'-phenylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
t-butyl 3- (3- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (3 '-(dimethylamino) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
t-butyl 3- (4'-methoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
3- (4 '-(benzyloxy) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (4'-bromobiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (3'-formylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
t-butyl 3- (2'-phenoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-yl carbonate;
3- (biphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
3- (3'-phenylbiphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-yl t-butyl carbonate;
2- (3- (4'-bromobiphenyl-4-yl) -5- (triisopropylsilyloxy) -1H-pyrazol-1-yl) pyridine;
2- (3- (biphenyl-4-yl) -5- (diphenylboryloxy) -1H-pyrazol-1-yl) pyridine;
3- (biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3 '-(dimethylamino) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (2- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3'-phenylbiphenyl-2-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4 '-(benzyloxy) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4'-bromobiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3 ′-(3-formylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (2'-phenoxybiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3'-phenylbiphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3- (naphthalen-1-yl) phenyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3 '-(dimethylamino) biphenyl-3-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4'-methoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4 '-(benzyloxy) biphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4'-bromobiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3'-formylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (2'-phenoxybiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (biphenyl-4-yl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol;
3- (4- (benzo [d] [1,3] dioxol-5-yl) phenyl) -1- (pyrimidin-2-yl) -1H-pyrazol-5-ol;
3- (3'-phenylbiphenyl-4-yl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3-phenyl-4-propyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;
4-benzyl-3-phenyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3-benzyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (o-bromobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (p-methoxybenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3-phenethyl-1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (p-chlorobenzyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (phenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (naphthalen-3-yloxy) methyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3-((4-chlorophenoxy) methyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3-((2,4-dichlorophenoxymethyl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
1- (pyridin-2-yl) -3-styryl-1H-pyrazol-5-ol;
3- (4-methoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3,4-dimethoxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3,4-dichlorostyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4- i -propylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4-trifluoromethylstyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol;
3- (3-methoxy-4-t-butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol;
3- (3,5-dimethoxy-4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-ol;
3- (3-methoxy-4- t -butyldimethylsilyloxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol;
3- (4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3,5-dimethoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazol-5-ol;
3- (3-methoxy-4-hydroxystyryl) -1- (pyridin-2-yl) -1H-pyrazole-5-thiol; And
4-((E) -2- (5-amino-1- (pyridin-2-yl) -1H-pyrazol-3-yl) vinyl) -2-methoxyphenol. The composition for preventing or treating cardiovascular disease according to claim 5, comprising at least one compound selected from the group consisting of the compounds listed below and their pharmaceutically acceptable salts.
Hydrochloride 278 of 1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -pyrazol-5-ol;
Hydrochloride 305 of 1- (pyridin-2-yl) -3-phenyl- 1H -pyrazole-5-ol;
1- (pyridin-2-yl) -3-phenyl-4-propyl- 1H -5 (isopropyloxycarbonyloxymethyloxy) pyrazole 306; And
Hydrochloride 308 of 1- (pyridin-2-yl) -3-[(3-methoxy-4-hydroxyphenyl) -E -ethenyl] -4-benzyl- 1H -pyrazole-5-ol. A method for removing vascular narrowing by administering the composition of any one of claims 1 to 6 to a subject other than a human. A compound of Formula 1, or a pharmaceutically acceptable salt thereof;
A compound of formula (I), or a pharmaceutically acceptable salt thereof; And
A drug delivery device for topical administration of a composition for the prevention or treatment of vascular restenosis comprising at least one of a compound of formula A, or a pharmaceutically acceptable salt thereof.

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